Enantioselective aldol reactions with aqueous 2,2

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dimethoxyacetaldehyde organocatalyzed by binam-prolinamides under solvent-free .... assigned according to the data of the same compound prepared by using ...
Tetrahedron: Asymmetry 25 (2014) 1323–1330

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Enantioselective aldol reactions with aqueous 2,2dimethoxyacetaldehyde organocatalyzed by binam-prolinamides under solvent-free conditions Fernando J. N. Moles, Abraham Bañón-Caballero, Gabriela Guillena ⇑, Carmen Nájera ⇑ Departamento de Química Orgánica, Facultad de Ciencias, and Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Apdo 99, 03080 Alicante, Spain

a r t i c l e

i n f o

a b s t r a c t

Article history: Received 17 July 2014 Accepted 20 August 2014

Aqueous 2,2-dimethoxyacetaldehyde (60% wt solution) is used as an acceptor in aldol reactions, with cyclic and acyclic ketones and aldehydes as donors, organocatalyzed by 10 mol % of N-tosyl-(Sa)binam-L-prolinamide [(Sa)-binam-sulfo-L-Pro] at rt under solvent-free conditions. The corresponding monoprotected 2-hydroxy-1,4-dicarbonyl compounds are obtained in good yields and with high levels of diastereo- and enantioselectivity mainly as anti-aldols. In the case of 4-substituted cyclohexanones a desymmetrization process takes place to mainly afford the anti,anti-aldols. 2,2-Dimethyl-1,3-dioxan5-one allows the synthesis of a useful intermediate for the preparation of carbohydrates in higher yield, de and ee than with L-Pro as the organocatalyst. Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction

compounds. This synthetic equivalent to protected glyoxal is available as 60% wt solution in water and has been used directly in the biomimetic organocatalyzed asymmetric synthesis of carbohydrates by means of aldol reactions.4 However, only a few examples using this aldehyde as an acceptor have been described. For the aldehyde–ketone aldol reaction,4a–i L-Pro in DMF4a,b or in DMSO,4c,d O-tert-Bu-L-threonine 14e in NMP and its derivative 2,4f primary amines such as the trans-cyclohexane-1,2-diamine derived catalyst 3 with TfOH4g and 4 with H3PW12O404h have been used as catalysts (Fig. 1). Hayashi et al. used L-Pro under solvent free conditions4i

Organocatalyzed direct aldol reactions have become a fundamental reaction in asymmetric synthesis.1 Since the pioneering work of List2 using L-proline as catalyst for intermolecular aldol reactions, a plethora of organocatalysts under several reaction conditions have been developed.3 The scope of ketones and aldehydes as donors and electrophiles has been extensively studied. Of special interest is the use of glyoxal dimethyl acetal as an acceptor for direct access to monoprotected 2-hydroxy-1,4-dicarbonyl OBut

OBut

H2N

CO2H

H2N

. TfOH

Ph Ph

O 1

N(C10H21)2

OH

H N

NH 2

Ph

3

2

F3C

O O N NH 2

CF3

n-C11H23 . H3PW12O 40

4

N H

CO2H

N H

CF3 HO

5 6

CF3

Figure 1. Organocatalysts used in aldol reactions with 2,2-dimethoxyacetaldehyde.

⇑ Corresponding authors. Tel.: +34 96 5903728; fax: +34 96 5903549. E-mail addresses: [email protected] (G. Guillena), [email protected] (C. Nájera). http://dx.doi.org/10.1016/j.tetasy.2014.08.012 0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.

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with moderate to high diastereo and enantioselectivity. On the other hand, for the aldehyde–aldehyde aldol reaction using glyoxal dimethyl acetal as an acceptor,4j–m different organocatalysts such as 4-hydroxy-L-proline derivative 5 in water,4j the diarylprolinol 64k in DMF and L-histidine in water4l,m have been employed (Fig. 1). In addition, L-Pro under solvent-free conditions has also been used for the aldol reaction of phenylpropanal.4i Our research group and also others have found that (Sa)-binamderived prolinamides 7–10 and their enantiomers5,6 have shown good catalytic activity in inter- and intramolecular aldol reactions in organic solvents, in aqueous media and especially under

solvent-free7 conditions (Fig. 2). Prolinamides 7 and 8 have been used as recoverable catalysts in intermolecular aldol reactions by a simple extractive acid–base work-up.5 On the other hand, N-tosyl-(Sa)-binam-L-prolinamides [(Sa)-binam-sulfo-L-Pro] 9a and 10a have shown their efficiency as general organocatalysts for inter- and intramolecular aldol reactions in water and under solvent-free conditions.6a–d However, in order to recover and to reuse them, they have to be covalently supported to polymers 9b and 10b6e and also 9c and 10c6f or in silica gel 9d and 10d6g (Fig. 2). Herein we report the application of binam-prolinamides as catalysts for the direct asymmetric aldol reaction of glyoxal

NH

NH

NH

O

NH

O

NH

O

NH

O

NH

NH (Sa)-binam-D-Pro 8

(Sa)-binam-L-Pro 7

NH

NH

NH

O

NH

NHTs

(Sa)-binamsulfo-L-Pro 9a

(Sa)-binamsulfo-D-Pro 10a

O

O

H N

NH NH

O

NHTs

NH NH

SO2

S

S

9b

10b

O

SO2

O

H N

NH

H N

H N

NH

NH

NH SO2

SO2 1

1

Ph 1

Ph

O

O

H

NH

O SiO2

O

O Si

S 3

O 9d

SiO2

O Si

S 3

O 10d

Figure 2. Binam-derived organocatalysts.

H N

NH

SO2

1

99

10c

N

NH NH

1

1

99

9c

SO2

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dimethyl acetal with different carbonyl compounds for the enantioselective and general synthesis of 2-hydroxy-1,4-dicarbonyl compounds. 2. Results and discussion Initial attempts were carried out using commercially available aqueous 60% wt solution of 2,2-dimethoxyacetaldehyde with 10 equiv of cyclohexanone (11c) and 20 mol % of the organocatalyst at rt under conventional magnetic stirring (Scheme 1 and Table 1). By using (Sa)-binam-L-Pro 7, the anti-aldol 12c was obtained quantitatively with 91% de and 88% ee after 1 d reaction time (Table 1, entry 1). The absolute configuration of 12c was assigned according to the data of the same compound prepared by using L-Pro as the catalyst.4i Diastereomeric catalyst (Sa)binam-D-Pro 8 afforded ent-12c in poorer results, 88% de and 72% ee, than 7 (Table 1, entry 2). In the case of (Sa)-binam-sulfo-L-Pro 9a and D-Pro 10a anti-12c was obtained after 1 d in 80% and 63% isolated yield, respectively, giving 9a with the best stereochemical results for 12c, 96% de and 97% ee (Table 1, entries 3 and 4, respectively), whereas ent-12a was obtained in lower 92% de and 91% ee using organocatalyst 10a (Table 1, entry 4). For the screening of the stoichiometry of the reaction 9a was used as the organocatalyst which showed that the amount of cyclohexanone 11c could be reduced to 2 equiv while still giving full conversion and similar stereochemical results (Table 1, compare entries 3 and 6). When the catalyst loading was reduced to 10 and 5 mol %, lower conversions were observed but with similar stereochemical results as with 20 mol % (Table 1, entries 7 and 8). Unfortunately, when using supported catalysts 9b and 9d (10 mol %) and 2 equiv of 11a for 7 d, the reaction failed (Table 1,

entries 9 and 10). Under the same reaction conditions, L-Pro afforded lower chemical yield (60%) and stereochemical results (80% de, 84% ee) than with 9a (Table 1, compare entries 7 and 11). In the case of Hayashi’s conditions, anti-12c was obtained, after 92 h reaction time and using 5 equiv of 11c and 30 mol % of L-Pro in 80% yield as a 10:1 diastereomer ratio and 93% ee.4i The influence of the reaction temperature was then determined. When the temperature was lowered to 0 °C the enantioselection for anti-12c remained essentially the same as to when working at 25 °C, but the reaction time increased from 1 to 2 d (Table 1, entry 12). The effect of acids as additives was studied with 5 mol % of catalyst 9a and 5 mol % loading of benzoic, 4-nitrobenzoic, acetic and dichloroacetic acids (Table 1, entries 13–16). In general similar results were obtained than without an additive (Table 1, compare entry 8 with entries 13–16). The scope of the aldol reaction with different cyclic ketones (2 equiv) were performed using 9a (10 mol %) at rt (Scheme 2 and Table 2). Cyclobutanone 11a showed a lower diastereoselectivity than cyclohexanone and afforded anti-12a in 34% de and modest 50% yield, although in 97% ee (Table 2, entry 1). On the other hand, cyclopentanone 11b afforded as mainly syn-12b in 62% de, which was higher than the 0% de obtained under L-Pro catalysis.4i The syn-aldol 12b was obtained in similar 95% ee than with L-Pro (93%)1i (Table 2, entry 2).4i In the case of six-membered cycloalkanones 11c–11f, products 12c–12f were obtained mainly as antiisomers in high yields, diastereo and enantioselectivities (Table 2, entries 3–6). However, cyclohexane-1,4-dione 11g gave the corresponding syn-12g in 48% de and with 96% ee (Table 2, entry 7). In the case of using the protected 1,3-dihydroxyacetone, 2,2dimethyl-1,3-dioxan-5-one 11h, the protected D-erythro-pentos4-ulose 12h was obtained in 96% de and with 92% ee (Table 2, entry 8). For the sake of comparison, L-Pro (30 mol %) gave after 13 h

O O

O

OMe +

MeO

R

T (ºC), t (d)

H

R1

OMe

cat.

O

O

OMe

OH 2

+

9a (10 mol%)

O

MeO

OMe

R1

rt

H

OMe

OH

OMe

R2

11a-k

12a-k

12c

11c

Scheme 1. Aldol reaction between cyclohexanone and 2,2-dimethoxyacetaldehyde.

Scheme 2. Aldol reaction dimethoxyacetaldehyde.

between

cycloalkanones

and

2,2-

Table 1 Screening and optimization of the reaction conditions for the enantioselective aldol reaction of 11c and 2,2-dimethoxyacetaldehyde

a b c d e

Entry

Cat. (mol %)

11c (equiv)

Additive (5 mol %)

1 2 3 4 5 6 7 8 9 10 11

7 (20) 8 (20) 9a (20) 10a (20) 9a (20) 9a (20) 9a (10) 9a (5) 9b (10) 9d (10)

10 10 10 10 5 2 2 2 2 2 2

12 13 14 15 16

9a 9a 9a 9a 9a

L-Pro

(10) (10) (5) (5) (5) (5)

2 2 2 2 2

Conva (%)

T (°C)

t (d)

— — — — — — — — — — —

25 25 25 25 25 25 25 25 25 25 25

1 1 1 1 1 1 1 1 7 7 2

100 100 90 75 100 100 88 75 — — 75

— PhCO2H 4-NO2–C6H4CO2H AcOH Cl2CHCO2H

0 25 25 25 25

2 1 1 1 1

100 75 69 73 71

Determined by 1H NMR (300 MHz). Isolated yield after column chromatography based on 2,2-dimethoxyacetaldehyde (0.25 mmol). anti/syn diastereomers, determined by 1H NMR (300 MHz). Determined by GC with a chiral column CP CHIRALSIL DEX CB. ent-12c was obtained.

Yieldb (%)

dec

eed (%)

— — 80 63 — — 78 — — — 60

91 88 96 92 93 92 99 96 — — 80

88 72e 97 91e 97 98 97 97 — — 84

82 — — — —

97 94 96 96 95

98 95 93 94 94

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Table 2 Enantioselective aldol reaction of cyclic ketones and 2,2-dimethoxyacetaldehyde catalyzed by (Sa)-binam-sulfo-L-Pro 9aa Entry

Product O

drc

eed,e (%)

50

67:33

97

48

74

14:86

95

12c

32

87

98:2

97

12d

50

82

97:3

95

12e

50

73

91:9

92

12f

48

66

99:1e

92e

12g

48

81

26:74

96

12h

48

68

98:2

92

12i

52

80

95:3:2:1

97f

12j

48

92

94:4:1:1

96

12k

48

93

96:2:1:1

95

No.

t (h)

12a

48

12b

Yieldb (%)

OH OMe

1

OMe O

OH OMe

2

OMe O

OH OMe

3

OMe O

OH OMe

4

OMe

O O

OH OMe

5

OMe

S O

OH OMe

6

OMe

N Boc O

OH OMe

7

OMe O O

OH OMe

8 O

O O

OMe OH OMe

9

OMe Ph O

OH OMe

10

OMe Me O

OH OMe

11

OMe But

a b c d e f

Reaction conditions: 60% wt aqueous 2,2-dimethoxyacetaldehyde (0.25 mmol), cycloalkanone (0.5 mmol) and 9a (10 mol %) at rt. Isolated yield after column chromatography based on 2,2-dimethoxyacetaldehyde. anti/syn diastereomers, determined by 1H NMR (300 MHz). Determined by GC with a chiral column CP CHIRALSIL DEX CB. For the major diastereomer. Determined by HPLC with a chiral column Chiralpak IA.

reaction time 12h in 47% yield, 90% de and with 83% ee under the same solvent-free conditions,4i whereas, L-Pro (30 mol %) in DMF at 2 °C gave 12h in 69% yield, 88% de and with 90% ee.4a Under similar reaction conditions using L-Pro (20 mol %) but at 4 °C, 12h was obtained in 60% yield, 18:1 dr and 98% ee.4b Similar results, 60% yield, 84% de and 96% ee have been obtained by using dry DMSO

at 5 °C in the presence of LiCl.4d When 4-substituted cyclohexanones 11i–k were used as donors, a concomitant desymmetrization took place and mainly gave anti,anti-aldols 12i–k in high yields, de and ee (Table 2, entries 9–11). Acyclic ketones 11l–p were allowed to react with 2,2-dimethoxyacetaldehyde under the same reaction conditions to give

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O

O

OMe +

O

MeO

rt

H

R

OH

O

R

OMe

anti-12l-o

11l-o

OH

OMe

9a (10 mol%)

OMe R

OMe iso -12l-o

Scheme 3. Aldol reaction between acyclic ketones and 2,2-dimethoxyacetaldehyde.

Table 3 Enantioselective aldol reaction of acyclic ketones and 2,2-dimethoxyacetaldehyde catalyzed by (Sa)-binam-sulfo-L-Pro 9aa Entry

Product O

anti/isoc

dec,d

eee,f (%)

55

.



99

4

48

10:90



95

12n

4

30

68:32

82

90

12o

4

49

58:42

90

94g

12p

4

53

90:10

80

97

No.

t (d)

12l

3

12m

Yieldb (%)

OH OMe

1

OMe O

OH OMe

2

OMe O

OH OMe

3

OMe

OMe O

OH OMe

4

OMe

OBn O

OH OMe

5 Cl a b c d e f g

OMe

Reaction conditions: 60% wt aqueous 2,2-dimethoxyacetaldehyde (0.25 mmol), alkanone (0.5 mmol) and 9a (10 mol %) at rt. Isolated yield after column chromatography based on 2,2-dimethoxyacetaldehyde. Determined by 1H NMR (300 MHz). anti/syn diastereomers. Determined by GC with a chiral column CP CHIRALSIL DEX CB. For the major diastereomer. Determined by HPLC with a chiral column Chiralpak IA.

aldols 12l–p (Scheme 3, Table 3). Acetone 11l gave aldol 12l with high 99% ee and moderate 55% yield (Table 3, entry 1). In the case of butan-2-one 11m, a 1:9 mixture of regioisomers 12m was obtained (Table 3, entry 2). The major iso-isomer was isolated in 48% yield and with 95% ee. When a-alkoxyacetones 11n and 11o were allowed to react with 2,2-dimethoxyacetaldehyde, anti- and iso-aldols 12n and 12o were obtained as 2:1 and 1:1 regioisomeric mixtures, respectively (Table 3, entries 3 and 4). The anti-aldols 12n and 12o were isolated in 82% and 90% de, respectively, and in 90% and 94% ee. A higher regioselectivity was observed in the

O

case of a-chloroacetone 11p affording aldol 12p as a 9:1 mixture of anti/iso regioisomers (Table 3, entry 5). The major anti-isomer 12p was isolated in 80% de and in 97% ee. The aldol reaction with a representative aldehyde, 3-phenylpropanal 13, afforded the corresponding aldol after 72 h reaction time, which was then submitted to a reduction with NaBH4 to give diol 14 in 64% yield as a mixture 4:1 of anti/syn diastereomers and with 97% ee for the anti-14 product (determined by HPLC) (Scheme 4). The same reaction catalyzed by L-Pro gave product 14 in 40% yield as a 3.3:1 anti/syn mixture and the anti-14 with 92% ee.4i 3. Conclusion

H CH2Ph

OH

13

OH OMe

1. 9a (10 mol%), rt

+

2. NaBH4, MeOH, 0 ºC

OMe

OMe

anti-14

O

MeO

PhCH2

H

Scheme 4. Aldol reaction dimethoxyacetaldehyde.

between

3-phenylpropanal

13

and

2,2-

It can be concluded that binam-prolinamides can be used as chiral catalysts to perform the aldol reaction of 2,2-dimethoxyacetaldehyde as an acceptor with cyclic and acyclic ketones as well as aldehydes under solvent-free conditions, just in the presence of 3.8 equiv of water from the aqueous 60% wt 2,2-dimethoxyacetaldehyde. From the assayed unsupported and supported binamderived organocatalysts, (Sa)-binam-sulfo-L-prolinamide showed the highest efficiency for this type of aldol reaction and was better than the previous described reactions with L-Pro under the same solvent-free conditions.

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4. Experimental 4.1. General Catalysts 7–10 were prepared according to the literature.2,3 All the reagents were commercially available and used without further purification. 1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were obtained at 25 °C using CDCl3 as solvent and chemical shifts are reported as d values relative to TMS as the internal standard. IR spectra were obtained with Jasco 4100 LE (Pike Piracle ATR). High resolution mass spectra (HRMS-ESI) were obtained on a Waters LCT Premier XE apfortus equipped with a time of flight (TOF) analyzer and the samples were ionized by ESI techniques and introduced through an ultra-high pressure liquid chromatography (UPLC) model Waters ACQUITY H CLASS. Optical rotations were measured on a Jasco P-1030 polarimeter with a 5 cm cell (c given in g/100 mL). GC analyses were performed on an Agilent Technologies 7820 GC System. HPLC analyses were performed on an Agilent 1100 series equipped with a chiral columns Chiralpak IA and Chiralpak AD-H, and automatic injector Agilent 1100, using mixtures of n-hexane/isopropyl alcohol (IPA) as mobile phase, at 25 °C. Analytical TLC was performed on silica gel plates and the spots were visualized using KMnO4 solution. For flash chromatography we employed silica gel 60 (0.040–0.063 mm). The absolute configurations of aldols 12b,c,h and diol 14 were assigned according to the literature data4i while the other aldols were assigned by analogy with the [a]26 D values. 4.2. General procedure for the aldol reaction To a mixture of the 2,2-dimethoxyacetaldehyde 60% wt aqueous solution (0.038 mL, 0.25 mmol) and organocatalyst 9a (10 mol %) at rt were added to the corresponding carbonyl compound (0.5 mmol). The reaction was stirred until 2,2-dimethoxyacetaldehyde was consumed (monitored by TLC). The resulting residue was purified by column chromatography on silica gel (hexanes/EtOAc) to yield the pure aldol product. 4.2.1. (S)-2-((R)-1-Hydroxy-2,2-dimethoxyethyl)cyclobutanone 12a Colorless oil (21 mg, 50%); [a]26 D = –5 (c 0.5, CHCl3, anti/syn: 67:33, eeanti 97% from GC); Rf = 0.32 (Hex/EtOAc: 1:1). IR: m 3642 (OH), 1579 (C@O). 1H NMR (300 MHz, CDCl3): d 4.55 (d, J = 7.1 Hz, 1H), 3.74 (dd, J = 7.0, 4.1 Hz, 1H), 3.68–3.53 (m, 1H), 3.48 (s, 3H), 3.48 (s, 3H), 3.06–2.95 (m, 2H), 2.24–2.05 (m, 3H). 13 C NMR (75 MHz, CDCl3, diastereomer mixture (60:40): d 210.3, 207.4, 105.1, 104.6, 77.2, 76.6, 70.5, 68.4, 61.4, 60.8, 56.1, 55.0, 45.9, 45.6, 13.3, 11.6. HRMS calcd for C8H14O4: 174.0892; found: 197.0790 (M++Na, recalculated 197.0790). GC: CP CHIRALSIL DEX CB column (140 °C, 13.4 Psi), Rt = 11.1 min (minor anti), Rt = 11.5 min (major anti), Rt = 19.6 min (syn). 4.2.2. (R)-2-((R)-1-Hydroxy-2,2-dimethoxyethyl)cyclopentanone 12b4i Yellow oil (35 mg, 74%); [a]26 50 (c 3, CHCl3, anti/syn: D = 14:86, eesyn 95% from GC); Rf = 0.34 (Hex/EtOAc: 1:1). IR: m 3555 (OH), 1623 (C@O). 1H NMR (300 MHz, CDCl3): d 4.30 (d, J = 6.8 Hz, 1H), 4.19 (dd, J = 6.6, 3.5 Hz, 1H), 3.48 (d, J = 3.0 Hz, 1H), 3.46 (s, 3H), 3.42 (s, 3H), 2.44–2.26 (m, 2H), 2.19–2.03 (m, 4H). 13C NMR (75 MHz, CDCl3): d 220.0, 105.0, 68.9, 54.5, 50.1, 38.6, 22.9, 20.8. MS (EI) m/z (%) for C9H16O4: M+ = 188 (3), 157 (10), 125 (10), 75 (100). GC: CP CHIRALSIL DEX CB column (140 °C, 13.4 Psi), Rt = 21.3 min (anti), Rt = 34.4 min (minor syn), Rt = 36.8 min (major syn).

4.2.3. (S)-2-((R)-1-Hydroxy-2,2-dimethoxyethyl)cyclohexanone 12c4i Colorless oil (44 mg, 87%); [a]26 12 (c 0.5, CHCl3, anti/syn: D = 98:2, eeanti 97% from GC); Rf = 0.37 (Hex/EtOAc: 1:1). IR: m 3473 (OH), 1699 (C@O). 1H NMR (300 MHz, CDCl3): d. 4.51 (d, J = 5.7 Hz, 1H), 3.63 (dd, J = 11.3, 5.6 Hz, 1H), 3.47 (s, 3H), 3.42 (s, 3H), 3.24 (d, J = 7.4 Hz, 1H), 2.71 (ddd, J = 9.9, 7.2, 4.4 Hz, 1H), 2.45–2.31 (m, 2H), 2.19–2.05 (m, 2H), 1.98–1.87 (m, 1H), 1.87– 1.67 (m, 3H). 13C NMR (75 MHz, CDCl3): d 215.0, 105.4, 73.0, 55.7, 54.4, 51.4, 43.0 (CH2), 31.6 (CH2), 27.9 (CH2), 24.9 (CH2). MS (EI) m/z (%) for C10H18O4: M+ = 202 (5), 184 (8), 139 (12), 75 (100). GC: CP CHIRALSIL DEX CB column (160 °C, 13.4 Psi), Rt = 5.9 min (minor anti), Rt = 6.1 min (major anti), Rt = 6.9 min (syn). 4.2.4. (S)-3-((R)-1-Hydroxy-2,2-dimethoxyethyl)dihydro-2H-pyran-4(3H)-one 12d Colorless oil (42 mg, 82%); [a]26 18 (c 0.8, CHCl3, anti/syn: D = 97:3, eeanti 95% from GC); Rf = 0.22 (Hex/EtOAc: 1:1). IR: m 3458 (OH), 1710 (C@O). 1H NMR (300 MHz, CDCl3): d 4.49 (d, J = 5.7 Hz, 1H), 4.18–4.07 (m, 2H), 3.86–3.78 (m, 2H), 3.75 (dd, J = 9.9, 4.9 Hz, 1H), 3.43 (s, 3H), 3.42 (s, 3H), 3.06 (d, J = 5.2 Hz, 1H), 2.91–2.81 (m, 1H), 2.64–2.43 (m, 2H). 13C NMR (75 MHz, CDCl3): d 208.9, 105.4, 70.5, 70.0, 68.1, 55.9, 54.6, 52.7, 43.0. HRMS calcd for C9H16O5: 204.0998; found: 227.0894 (M++Na, recalculated 227.0895). GC: CP CHIRALSIL DEX CB column (130 °C, 13.4 Psi), Rt = 25.9 min (minor anti), Rt = 26.3 min (major anti), Rt = 31.8 min (minor syn), Rt = 32.8 min (major syn). 4.2.5. (S)-3-((R)-1-Hydroxy-2,2-dimethoxyethyl)dihydro-2H-thiopyran-4(3H)-one 12e Yellow oil (40 mg, 73%); [a]26 47 (c 3.8, CHCl3, anti/syn: 91:9, D = eeanti 97% from GC); Rf = 0.29 (Hex/EtOAc: 1:1). IR: m 3460 (OH), 1704 (C@O). 1H NMR (300 MHz, CDCl3): d 4.49 (d, J = 5.5 Hz, 1H), 3.90 (dd, J = 10.2, 6.8 Hz, 1H), 3.47 (s, 3H), 3.45 (s, 3H), 3.09–3.04 (m, 2H), 3.05–2.96 (m, 2H), 2.95 (d, J = 6.8 Hz, 1H), 2.83–2.72 (m, 4H). 13C NMR (75 MHz, CDCl3): d 211.3, 105.6, 72.1, 55.8, 54.7, 53.9, 44.6, 33.4, 30.6. HRMS calcd for C9H16O4S: 220.0769; found: 243.0657 (M++Na, recalculated 243.0667). GC: CP CHIRALSIL DEX CB column (160 °C, 13.4 Psi), Rt = 34.6 min (minor anti), Rt = 35.5 min (major anti). 4.2.6. (S)-tert-Butyl-3-((R)-1-hydroxy-2,2-dimethoxyethyl)-4-oxopiperidin-1-carboxylate 12f Colorless oil (55 mg, 66%); [a]26 20 (c 1.2, CHCl3, anti/syn: D = 99:1, eeanti 92% from GC); Rf = 0.2 (Hex/EtOAc: 1:1). IR: m 3435 (OH), 1689 (C@O). 1H NMR (300 MHz, CDCl3): d 4.52 (d, J = 5.6 Hz, 1H), 4.05 (dd, J = 13.5, 5.7 Hz, 1H), 3.79–3.65 (m, 2H), 3.47–3.39 (m, 8H), 3.00–2.84 (m, 1H), 2.80–2.68 (m, 1H), 2.57– 2.37 (m, 2H), 1.47 (s, 9H). 13C NMR (75 MHz, CDCl3): d 210.0, 154.6, 80.5, 70.8, 55.9, 54.7, 54.4, 51.1, 43.1, 41.4, 41.1, 28.3. HRMS calcd for C14H25NO6: 303.1682; found: 326.1581 (M++Na, recalculated 326.1580). HPLC: Chiralpak IA column (98% hexane, 2% PriOH, 25 °C, 1 mL/min, 230 nm), Rt = 30.0 min (major anti), Rt = 33.6 min (syn), Rt = 40.3 min (minor anti). 4.2.7. (R)-2-((R)-1-Hydroxy-2,2-dimethoxyethyl)cyclohexane-1, 4-dione 12g Brown oil (43 mg, 81%); [a]26 18 (c 1.2, CHCl3, anti/syn: D = 26:74, eesyn 96% from GC); Rf = 0.35 (Hex/EtOAc: 1:1). IR: m 3429 (OH), 1707 (C@O). 1H NMR (300 MHz, CDCl3): d 4.57 (d, J = 6.8 Hz, 1H), 4.28 (dd, J = 15.7, 6.8 Hz, 1H), 3.76 (dt, J = 6.6, 3.2 Hz, 1H), 3.47–3.42 (m, 6H), 3.00–2.59 (m, 7H). 13C NMR (75 MHz, CDCl3, diastereomer mixture 1:1): d 209.7, 208.6, 104.9, 104.1, 73.2, 69.6, 56.0, 55.0, 54.8, 54.7, 47.1, 47.0, 37.9, 37.4, 37.1, 36.1, 36.0. HRMS calcd for C10H16O5: 216.0998; found: 239.0839 (M++Na, recalculated 239.0837). GC: CP CHIRALSIL DEX

F.J.N. Moles et al. / Tetrahedron: Asymmetry 25 (2014) 1323–1330

CB column (180 °C, 13.4 Psi), Rt = 21.4 min (minor anti), Rt = 5.8 min (major syn), Rt = 24.7 min (minor syn), Rt = 25.3 min (major anti). 4.2.8. (S)-4-((R)-1-Hydroxy-2,2-dimethoxyethyl)-2,2-dimethyl1,3-dioxan-5-one 12h4i Colorless oil (39 mg, 68%); [a]26 12 (c 0.6, CHCl3, anti/syn: D = 98:2, eeanti 92% from GC); Rf = 018 (Hex/EtOAc: 1:1). IR: m 3449 (OH), 1748 (C@O). 1H NMR (300 MHz, CDCl3): d 4.68 (d, J = 6.8 Hz, 1H), 4.49 (dd, J = 13.9, 1.3 Hz, 1H), 4.36–3.92 (m, 4H), 3.50–3.44 (m, 6H), 1.50 (s, 6H). 13C NMR (75 MHz, CDCl3): d 206.5, 103.2, 76.0, 71.1, 67.0, 55.3, 54.3, 25.3, 24.9, 22.9. MS (EI) m/z (%) for C10H16O6: M+ = 54 (3), 219 (5), 171 (10), 129 (15), 75 (100). GC: CP CHIRALSIL DEX CB column (150 °C, 13.4 Psi), Rt = 9.1 min (major anti), Rt = 9.8 min (minor anti), Rt = 17.8 min (minor syn), Rt = 18.9 min (major syn). 4.2.9. (2S,4S)-2-((R)-1-Hydroxy-2,2-dimethoxyethyl)-4-phenylcyclohexanone 12i Colorless oil (55 mg, 80%); [a]26 40 (c 1.6, CHCl3, dr: D = 95:3:2:1, eeanti 97% from HPLC); Rf = 0.36 (Hex/EtOAc: 1:1). IR: m 3439 (OH), 1704 (C@O). 1H NMR (300 MHz, CDCl3): d 7.45–7.17 (m, 5H), 4.34 (d, J = 6.0 Hz, 1H), 3.89 (dd, J = 5.2, 4.7 Hz, 1H), 3.50 (s, 3H), 3.49 (s, 3H), 3.44–3.35 (m, 1H), 2.83–2.76 (m, 1H), 2.72 (d, J = 4.1 Hz, 1H), 2.69–2.62 (m, 1H), 2.56–2.47 (m, 1H), 2.28– 2.02 (m, 4H). 13C NMR (75 MHz, CDCl3): d 213.1, 144.6, 128.6, 126.8, 126.4, 105.7, 73.4, 56.1, 55.2, 49.7, 41.0, 38.0, 37.0, 32.8. HRMS calcd for C16H22O4: 278.3435; found: 279.1592 (M++H, recalculated 279.1596). HPLC: Chiralpak IA column (98% hexane, 2% PriOH, 25 °C, 1 mL/min, 210 nm), Rt = 24.7 min (minor anti), Rt = 26.4 min (major anti). 4.2.10. (2S,4S)-2-((R)-1-Hydroxy-2,2-dimethoxyethyl)-4-methylcyclohexanone 12j Colorless oil (49 mg, 92%); [a]26 80 (c 2.5, CHCl3, dr: D = 94:4:1:1, eeanti 96% from GC); Rf = 0.4 (Hex/EtOAc: 1:1). IR: m 3489 (OH), 1738 (C@O). 1H NMR (300 MHz, CDCl3): d 4.36 (d, J = 5.9 Hz, 1H), 3.68 (dd, J = 10.8, 5.6 Hz, 1H), 3.44 (s, 3H), 3.43 (s, 3H), 2.87 (d, J = 5.7 Hz, 1H), 2.72 (dd, J = 12.5, 6.1 Hz, 1H), 2.48– 2.33 (m, 2H), 2.24–2.11 (m, 1H), 2.08–1.88 (m, 2H), 1.74–1.51 (m, 2H), 1.08 (d, J = 6.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 214.4, 105.4, 73.1, 57.7, 54.8, 48.3, 39.7, 37.7, 33.8, 27.1, 19.7. HRMS calcd for C11H20O4: 216.1362; found: 239.1248 (M++Na, recalculated 239.1259). GC: CP CHIRALSIL DEX CB column (120 °C, 13.4 Psi), Rt = 50.7 min (minor), Rt = 51.9 min (major). 4.2.11. (2S,4S)-4-(tert-Butyl)-2-((R)-1-hydroxy-2,2-dimethoxyethyl)-cyclohexanone 12k Colorless oil (60 mg, 93%); [a]26 100 (c 3, CHCl3, dr: 96:2:1:1, D = eeanti 95% from GC); Rf = 0.31 (Hex/EtOAc: 1:1). IR: m 3439 (OH), 1703 (C@O). 1H NMR (300 MHz, CDCl3): d 4.30 (d, J = 5.7 Hz, 1H), 3.79 (dd, J = 10.8, 5.6 Hz, 1H), 3.44 (s, 6H), 2.74 (d, J = 4.9 Hz, 1H), 2.65 (dd, J = 10.4, 5.2 Hz, 1H), 2.47–2.34 (m, 2H), 2.06–1.92 (m, 2H), 1.72–1.61 (m, 2H), 1.54–1.41 (m, 1H), 0.88 (s, 9H). 13C NMR (75 MHz, CDCl3): d 214.7, 105.8, 72.6, 55.9, 55.0, 49.5, 42.2, 40.6, 32.6, 29.6, 27.3, 26.0. HRMS calcd for C14H26O4: 258.1831; found: 281.1725 (M++Na, recalculated 281.1729). GC: CP CHIRALSIL DEX CB column (150 °C, 13.4 Psi), Rt = 69.3 min (major), Rt = 71.6 min (minor). 4.2.12. (R)-4-Hydroxy-5,5-dimethoxypentan-2-one 12l Colorless oil (22 mg, 55%); [a]26 35 (c 0.8; CHCl3, ee 99% from D = GC); Rf = 0.3 (Hex/EtOAc: 1:1). IR: m 3561 (OH), 1628 (C@O). 1H NMR (300 MHz, CDCl3): d 4.26 (d, J = 5.3 Hz, 1H), 4.14 (dd, J = 5.7, 2.9 Hz, 1H), 3.47 (s, 3H), 3.46 (s, 3 H), 2.83 (d, J = 3.2 Hz, 1H), 2.74 (dd, J = 17.1, 3.7 Hz, 1H), 2.66 (dd, J = 17.1, 8.3 Hz, 1H), 2.22

1329

(s, 3H). 13C NMR (75 MHz, CDCl3): d 208.7, 106.0, 68.0, 55.8, 55.1, 44.7, 30.8. HRMS calcd for C7H14O4: 162.0900; found: 185.0794 (M++Na, recalculated 185.0790). GC: CP CHIRALSIL DEX CB column (160 °C, 13.4 Psi), Rt = 3.6 min (minor), Rt = 5.1 min (major). 4.2.13. (R)-5-Hydroxy-6,6-dimethoxyhexan-3-one iso 12m Yellow oil (19 mg, 43%); [a]26 20 (c 0.5, CHCl3, ee 95% from D = GC); Rf = 0.25 (Hex/EtOAc: 1:1). IR: m 3428.1 (OH), 1592.9 (C@O). 1 H NMR (300 MHz, CDCl3): d 4.27 (d, J = 5.3 Hz, 1H), 4.19–4.10 (m, 1H), 3.46 (s, 3H), 3.45 (s, 3H), 2.87 (d, J = 4.0 Hz, 1H), 2.72 (dd, J = 17.0, 4.1 Hz, 1H), 2.63 (dd, J = 17.0, 7.9 Hz, 1H), 2.50 (c, J = 7.3 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H). 13C NMR (75 MHz, CDCl3): d 211.4, 106.0, 68.1, 55.7, 55.1, 43.4, 36.9, 7.6. HRMS calcd for C8H16O4: 176.1049; found: 177.1122 (M++H, calcd 177.1127). GC: CP CHIRALSIL DEX CB column (140 °C, 13.4 Psi), Rt = 6.9 min (minor), Rt = 7.4 min (major). 4.2.14. (3S,4R)-4-Hydroxy-3,5,5-trimethoxypentan-2-one 12n Yellow oil (14 mg, 30%); [a]26 18 (c 0.8, CHCl3, anti/syn: 91:9, D = eeanti 90% from GC); Rf = 0.2 (Hex/EtOAc: 1:1). IR: m 3599 (OH), 1591 (C@O). 1H NMR (300 MHz, CDCl3): d 4.43 (d, J = 6.7 Hz, 1H), 3.98 (dd, J = 5.2, 1.5 Hz, 1H), 3.80 (d, J = 3.7 Hz, 1H), 3.50 (s, 3H), 3.47 (m, 5H), 3.41 (s, 3H), 2.5 (s, 3H). 13C NMR (75 MHz, CDCl3): d 171.2, 103.2, 87.2, 77.2, 60.4, 21.1, 14.2. HRMS calcd for C8H16O5: 192.0998; found: 215.0888 (M++Na, recalculated 215.0895). GC: LIPODEX-A column (140 °C, 13.4 Psi), Rt = 10.1 min (minor), Rt = 10.4 min (major). 4.2.15. (3S,4R)-3-(Benzyloxy)-4-hydroxy-5,5-dimethoxypentan2-one 12o Brown oil (33 mg, 49%); [a]26 28 (c 1.0, CHCl3, anti/syn: 95:5, D = eeanti 94% from HPLC); Rf = 0.15 (Hex/EtOAc; 1:1). IR: m 3453 (OH), 1530 (C@O). 1H NMR (300 MHz, CDCl3): d 7.41–7.31 (m, 5H), 4.72 (d, J = 11.7 Hz, 1H), 4.59 (d, J = 11.7 Hz, 1H), 4.47 (d, J = 6.1 Hz, 1H), 4.01 (d, J = 3.1 Hz, 1H), 3.43 (s, 3H), 3.39 (s, 3H), 2.24 (s, 3H). 13C NMR (75 MHz, CDCl3): d 208.5, 173.3, 128.5, 128.0, 103.1, 84.7, 73.3, 72.4, 55.5, 54.5, 27.3. HRMS calcd for C14H20O5: 268.131; found: 291.1197 (M++Na, recalculated 291.1208). HPLC: Chiralpak AD-H column (90% hexane, 10% PriOH, 25 °C, 1 mL/min, 210 nm), Rt = 9.5 min (minor), Rt = 11.2 min (major). 4.2.16. (3S,4S)-3-Chloro-4-hydroxy-5,5-dimethoxypentan-2-one 12p Colorless oil (26 mg, 53%); [a]26 26 (c 1.1, CHCl3, anti/syn: D = 90:10, eeanti 97% from GC); Rf = 0.21 (Hex/EtOAc; 1:1). IR: m 3588 (OH), 1541 (C@O). 1H NMR (300 MHz, CDCl3): d 4.51 (d, J = 4.6 Hz, 1H), 4.40 (d, J = 5.4 Hz, 1H), 4.12 (m, 1H), 3.51 (s, 3H), 3.46 (s, 3H), 2.83 (d, J = 5.8 Hz, 1H), 2.37 (s, 3H). 13C NMR (75 MHz, CDCl3): d 202.1, 103.6, 73.3, 62.5, 56.0, 55.6, 27.8. HRMS calcd for C7H13ClO4: 196.0502; found: 219.0408 (M++Na, recalculated 219.0408). GC: LIPODEX-E column (140 °C, 13.4 Psi), Rt = 12.5 min (minor), Rt = 13.4 min (major). 4.2.17. (2S,3R)-2-Benzyl-4,4-dimethoxybutane-1,2-diol 144i After the aldol reaction took place, the crude product was diluted with MeOH (1 mL) then NaBH4 (38 mg, 1 mmol) was added at 0 °C and the mixture was stirred for 1 h at rt. The resulting residue was purified by flash chromatography (Hex/EtOAc: 1:1) to yield the anti/syn (7:1) diastereomeric mixture, as a colorless oil (38 mg, 64%); Rf = 0.37 (Hex/EtOAc: 1:1). IR: m 3420, 2933, 1060. 1 H NMR (anti-product, 400 MHz, CDCl3) d 7.30–7.20 (m, 5H), 4.44 (d, J = 6.8 Hz, 1H), 3.84 (dd, J = 8.6, 5.7 Hz, 1H), 3.69 (m, 1H), 3.63 (m, 1H), 3.44 (s, 3H), 3.32 (s, 3H), 2.87 (s, 1H), 2.85 (s, 1H), 2.73 (br s, 1H), 2.60 (br s, 1H), 2.12–2.00 (m, 1H). 13C NMR (anti-product, 101 MHz, CDCl3) d 140.1, 129.2, 128.4, 126.1, 105.1, 73.2, 62.4, 55.1, 54.4, 42.1, 35.1. HPLC (anti-product): Chiralpak AD-H

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column (97% hexane, 3% PriOH, 25 °C, 1 mL/min, 210 nm), Rt = 27.6 min (minor), Rt = 31.3 min (major). Acknowledgments We thank the financial support from the Spanish Ministerio de Economía y Competitividad (MINECO, Projects CTQ2010-20387 and Consolider Ingenio 2010, CSD2007-00006), FEDER, the Generalitat Valenciana (Prometeo/2009/039), the University of Alicante and the European Commission (ORCA action CM0905). A.B.-C. thanks Spanish MINECO for a predoctoral fellowship (FPU AP2009-3601). References 1. (a) Modern Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2004; (b) Modern Methods in Stereoselective Aldol Reactions; Mahrwald, R., Ed.; Wiley-VCH: Weinheim, 2013; (c) Science of Synthesis, Asymmetric Organocatalysis 1, Lewis Base and Acid Catalysts; List, B., Ed.; Thieme: Stuttgart, 2012. 2. List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395–2396. 3. For recent reviews, see: (a) Trost, B. M.; Brindle, C. S. Chem. Soc. Rev. 2010, 39, 1600–1632; (b) Panday, S. K. Tetrahedron: Asymmetry 2011, 22, 1817–1847; (c) Guillena, G.; Nájera, C.; Ramón, D. J. In Enantioselective Organocatalyzed Reactions; Mahrwald, R., Ed.; Springer: Heidelberg, 2011; (d) Heravi, M. M.; Asadi, S. Tetrahedron: Asymmetry 2012, 23, 1431–1465. 4. (a) Grondal, C.; Enders, D. Tetrahedron 2006, 62, 329–337; (b) Suri, J. T.; Mitsumori, S.; Albertshofer, K.; Tanaka, F.; Barbas, C. F., III J. Org. Chem. 2006, 71, 3822–3828; (c) Niewczas, I.; Majewski, M. Eur. J. Org. Chem. 2009, 33–37; (d) Palyam, N.; Niewczas, I.; Majewski, M. Synlett 2012, 2367–2370; (e) Utsumi, N.; Imai, M.; Tanaka, F.; Ramasastry, S. S. V.; Barbas, C. F., III Org. Lett. 2007, 9, 3445–

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